The present invention generally relates to methods and apparatus for the parallel synthesis of large numbers of molecularly diverse compounds. The present invention is particularly useful in generating combinatorial libraries of chemical compounds by simultaneously employing solid phase synthesis in a plurality of reaction vessels.
A standard method for searching for new chemical compounds employs the screening of pre-existing compounds in assays which have been designated to test particular properties of the compound being screened. Similarly, in designing compounds having desired physiochemical properties for general chemical applications, numerous compounds must be individually prepared and tested.
To reduce the time and expense involved in preparing and screening a large number of compounds for biological activity or for desirable physiochemical properties, technology has been developed for providing libraries of compounds for the discovery of lead compounds. Current methods for generating large numbers of molecularly diverse compounds focus on the use of solid phase synthesis. The generation of combinatorial libraries of chemical compounds by employing solid phase synthesis is well known in the art. For example, Geysen, et al. (Proc. Natl. Acad. Sci. USA, 3998 (1984) describe the construction of multi-amino acid peptide libraries; Houghton, et al. (Nature, 354, 84 (1991) and PCT Patent Pub. No. WO 92/09300) describe the generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery; Lam, et al. (Nature,354, 82 (1991) and PCT Patent Pub. No. WO 92/00091) describe a method of synthesis of linear peptides on a solid support such as polystyrene or polyacrylamide resin.
The growing importance of combinatorial chemistry as an integral component of the drug discovery process has spurred extensive technological and synthetic advances in the field (Thompson, L. A.; Ellman, J. A. (1996) Chem. Rev. 96, 555-600). Founded in peptide synthesis devised by Merrifield, solid phase chemistry has emerged as the prominent method for construction of small molecule combinatorial libraries (see e.g. Merrifield, R. B. (1963) J. AM. Chem. Soc. 85, 2149-2154; (a) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. (1995) Tetrahedron 51(30), 8135-8173. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. (1994) J. Med. Chem. 37, 1385-1401.).
To aid in the generation of chemical compounds, such as present combinatorial chemical libraries, scientific instruments should be developed which automatically perform many or all of the steps required to generate such compounds. In the past, multiple solid phase reactions have been conducted by heating a substrate attached to resin beads with appropriate reagents and solvents in a test tube immersed in a hot oil bath with rotating magnetic stir bar. Draining was accomplished by pouring the contents of the test tube through a filter. Back and forth operation between reacting and draining operation was very tedious and potentially exposed the reaction mixture to air.
Certain chemical processes require that the chemical reagents be kept under an inert or anhydrous atmosphere to prevent reactive groups from reacting with molecular oxygen, water vapor, or other agents commonly found in air. Working with repeated solvent and reagent washes in a number of reaction vessels was time consuming and possibly compromised the inert atmosphere in the reaction vessels. Conventional septum type devices may loose seal integrity after repeated penetrations by needles during such synthesis. Accordingly, there is a need for systems and methods for rapid synthesis of chemical compounds.